P758: INHIBITION OF ATR WITH CERALASERTIB (AZD6738) FOR THE TREATMENT OF PROGRESSIVE OR RELAPSED MYELODYSPLASTIC SYNDROMES AND CHRONIC MYELOMONOCYTIC LEUKEMIA: A PHASE IB/II STUDY
Authors: A. Brunner, Y. Liu, L. Mendez, J. Garcia, P. Amrein, D. Neuberg, E. Dean, S. Smith, R. Stone, A. Fathi, M. Walter, T. Graubert, M. Jacoby
Journal: HemaSphere (2022)

Background: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are enriched for mutations in the spliceosome complex, including the genes SF3B1, SRSF2, ZRSR2, and U2AF1. Ceralasertib (AZD6738) is a selective and potent inhibitor of Ataxia Telangiectasia and Rad3 Related (ATR) kinase. We have previously shown that cells with splicing factor (SF) mutations have increased R loops, which require ATR for resolution and preferentially undergo apoptosis after ATR inhibition. Aims: We hypothesized that inhibition of ATR may be useful in patients with MDS or CMML, particularly those who harbor SF gene mutations. Methods: This 2-part study evaluated ceralasertib monotherapy in adult patients with MDS or CMML progressing on or not responsive to front-line therapy (DNMTI for HR MDS, ESA for LR MDS). Enrollment cohorts included SF mutant (SF3B1, SRSF2, U2AF1, or ZRSR2) and SF wildtype (wt). Part 1 enrolled 3-6 patients at de-escalating dose levels: 160mg BID days 1-14 of 28 d cycles, 120mg BID d1-14, and 80mg BID d1-14. DLTs were assessed the first 30d and de-escalation would occur for DLTs in >1/6 patients. Higher-risk MDS (HR-MDS, IPSS-R > 3.5) and CMML patients were enrolled first; after a dose was deemed safe, lower-risk MDS (LR-MDS, IPSS-R 3.5, transfusion-dependent post/ineligible for ESA or severe neutropenia/thrombocytopenia) was evaluated. Part 2 enrolled up to 20 SF mut patients and 20 SF wt patients for efficacy. A Simon 2-stage design mandated that at least 1/10 patients in each group needed to respond (by IWG 2006 criteria) to enroll the final 10 patients. Results: At the data cut-off (12/15/21) 32 patients have been enrolled with 30 evaluable: 22 with HR-MDS or CMML, and 8 with LR-MDS. The median age was 73 (range 43-88) and predominantly male (26/30). 21 patients harbored SF mut disease while 9 had SF wt MDS/CMML. The most frequently seen ≥grade 3 adverse events (AEs) for higher-risk patients (n=20) included anemia (n=6), febrile neutropenia (n=4), neutropenia (n=5), thrombocytopenia (n=6). In LR-MDS (n=8), ≥grade 3 AEs included thrombocytopenia (n=2), and neutropenia (n=2). 5 deaths occurred within 30d of study treatment; 1 patient with active CMML had an intracranial bleed with thrombocytopenia, possibly related to study treatment, while 4 deaths were attributed to underlying disease (3 with progression to AML, 1 MDS patient with sepsis). No DLTs were observed in the HR or LR groups and 160mg BID days 1-14 of 28 days was deemed the RP2D. Responses were assessed across the cohort as well as according to SF mutant status (Table). A total of 8 patients had an IWG response (BOR: CR, n=1; mCR, n=3; HI, n=4), including 6/21 SF mut patients (ORR 29%), and 2/9 SF wt patients (ORR 22%). The responses in SF wt patients included one mCR (5% to 1% marrow blasts in a patient with DNMT3A and ETV6 mut and del(chr7)), and one HI-P (82 BL to 234 max in a patient with DNMT3A, IDH2, ETV6 mut and del(chr7)). Responses in SF mut included CR (n=1), mCR (n=2, one with associated HI-N), SD with HI (n=3). An additional 3 SF mut patients had improvements in blood counts but not lasting 8 weeks (ANC n=2, platelets n=1) and one with platelet improvement but a baseline not meeting IWG criteria (plt avg=108k prior to C1D1). Image:Summary/Conclusion: Ceralasertib is an oral ATR inhibitor with preliminary activity in patients with progressive/refractory MDS and CMML at doses of 160mg BID on days 1-14 of a 28 day cycle. The study is ongoing and will evaluate additional dosing schedules.